Advanced prostate cancer is an incurable and terminal disease which is characterized by metastasis and castration resistance. The mechanisms of progression to this advanced state are largely unknown. Our long term goal is to identify and characterize pathways which cause this lethal form of prostate cancer. We believe that novel discoveries in this focused area will have significantly impact on the prognosis and treatment of prostate cancer. MicroRNAs are a new class of regulatory molecules which control cellular pathways through post-transcriptional mechanisms. We have identified miR-21 as an Androgen-Receptor-regulated and oncogenic microRNA which is elevated in human prostate cancer. Importantly, miR-21 is sufficient to drive castration resistant tumor growth. In light of these discoveries, and the existing knowledge of miR-21 in other malignancies, we hypothesize that the miR-21 gene locus contributes to the development of advanced prostate cancer. The overall objective of this proposal are to (i) characterize the mechanisms of elevated miR-21 gene expression in human prostate cancer, (ii) to elucidate the pathways utilized by the miR-21 gene locus to promote cancer progression, and to compare miR-21 gene copy number and expression between human prostate cancers which have either been cured by primary therapy or recurred, progressed to metastasis, or castration resistance. PUBLIC HEALTH RELEVANCE: Prostate cancer (PCa) is a health problem of major significance in the United States. PCa strikes over 180,000 American men each year and accounts for approximately 10% of male cancer related deaths1. Despite an escalating research effort, there have been little to no advances in the treatment of metastatic and Castration Resistant Prostate Cancer (CRPC). Moreover, approximately 1/3rd of mean will recur following primary therapy2. Nonetheless, many men diagnosed with PCa will never develop the lethal or even symptomatic form of the disease within their lifetime3. Therefore, there are two major deficiencies in the current management of PCa: (1) Systemic Therapy - the lack of a successful therapy for CRPC and (2) Prognosis - the inability to consistently predict which cancers will progress. This grant application addresses these deficiencies by proposing studies of a novel pathway in CRPC and correlating genes in this pathway with disease recurrence and progression.